(T1430-10-54) Drug Particle Size Change of a Hydrophobic Drug and Its Impact on Dissolution after Twin-Screw Wet Granulation

Purpose: Twin-screw wet granulation (TSWG) evolvingly replaces high-shear wet granulation (HSWG). As a continuous manufacturing process, TSWG is more time- and material-sparing in formulation process development than HSWG. The powder property improvement by TSWG has been widely studied but not the dissolution behavior. In this study, we (1) compared the dissolution of high drug loading tablets made after TSWG and HSWG, using a hydrophobic drug as the model drug, (2) investigated the critical material attribute that affects tablet dissolution, (3) optimized the TSWG process to ensure quick tablet dissolution.

Methods: We found drastic drug particle size reduction during TSWG which did not occur by high shear wet granulation (HSWG). The drug particle size distribution was measured by laser diffraction in an aqueous suspension. This aqueous suspension was prepared by mixing TSWG granules into the drug saturated aqueous solution, in which most excipients dissolved, and drug particles were liberated into individual particles.

Results: The D10, D50, and D90 of received drug were 5.1 µm, 13 µm, and 27 µm, while after TSWG drastically reduced to 0.48 µm, 3.38 µm, and 12.24 µm, respectively. The calculated surface area of drug particles increased from 0.14 m²/g to 1.34 m²/g after TSWG. Since dissolution is correlated with drug particle size, it is necessary to evaluate and understand the impact of particle size reduction on tablet dissolution performance. Although TSWG granules release drug quicker than HSWG granules, TSWG tablets release drug slower than HSWG tablets. This slow tablet dissolution was attributed to slower tablet disintegration of TSWG tablets. Micro CT showed that water penetration was slower into the TSWG tablet cores. It could have been caused by the increased tortuosity in TSWG tablets that slowed down the water penetration. Therefore, the slow water penetration in TSWG tablets impart slow tablet disintegration. The level of drug particle size reduction was insensitive to screw speed, throughput, and liquid/solid ratio in TSWG. Screw design/geometry has been found to be the critical process parameter that caused different levels of size reduction. We optimized TSWG screw design by varying the number of kneading discs and replacing kneading discs by distributive mixing elements. The drug particle size in granules decreased from 13 µm in D50 to different levels, ranging from 1 µm to 10 µm in D50.

Conclusion: In conclusion, the drug particles in granules could decrease to different levels after TSWG by using different screw designs. Due to the drug hydrophobicity, the finer drug particles formed a barrier that decelerated water penetration into tablets, causing slower tablet disintegration, and eventually slower tablet dissolution. The drug particle size change could be minimized by reducing the number of mixing screw elements. The potential benefit of drug particle size reduction in dissolution is projected to be realized when the tablet disintegration is improved in further formulation and process development.

Acknowledgements: AbbVie Inc. funded the study. AbbVie was responsible for the study design, research, analysis, data collection, interpretation of data, and writing, reviewing, and approving of the publication. All authors are current employees of AbbVie and may own AbbVie stock.